The central melanocortin system is a fundamental regulator of food intake and body weight in rodents and humans. Moreover, central melanocortin pathways regulate insulin secretion and insulin sensitivity in key insulin target tissues including skeletal muscle. These findings suggest that the central melanocortin system is a fundamental regulator of the autonomic nervous system. Despite the importance of the melanocortin system, relatively little is known about the sites that express melanocortin receptors (MC3 and MC4-Rs) and where they project. Furthermore, it is not known if MC4-Rs are expressed in neurons in key autonomic and neuroendocrine regulatory sites and if MC4-R expressing neurons themselves innervate these key autonomic regulatory sites. In the current proposal we offer a neuroanatomic model detailing mechanisms by which the central melanocortin system regulates the sympathetic and parasympathetic nervous systems. The experiments offered are designed to directly test the components of our model. We will first determine which neural populations of MC4-R project to hindbrain and spinal cord nuclei, which are known to regulate autonomic function. Furthermore, we will chemically classify these MC4-R projecting neurons. Next, we will investigate if these neurons projecting to sympathetic preganglionic neurons are activated by leptin and MT-II administration. Finally, we will reactivate expression of MC4-R in hypothalamic neurons innervating autonomic preganglionic neurons under the control of a specific [unreadable] neuropeptide promoter in order to determine that MC4-R in hypothalamic neurons innervating autonomic preganglionic neurons (compared with obese MC4-R -/- mice) are critical in the regulation of food intake and energy expenditure. [unreadable] [unreadable]